Adenosine triphosphate (ATP) is known to serve as a source of energy in cells and a substrate of phosphorylation, as well as an extracellular messenger. It is known that ATP is released from a cell by various stimulation such as cellular injury, inflammation, nociceptive stimulus, reduced blood oxygen level, and also known to be released together with another messenger from a primary sensory nerve terminal. ATP thus released mediates various extracellular signal transductions through an ATP receptor (Non-Patent Document 4, Non-Patent Document 5).
ATP receptor is categorized into ionotropic P2X family and G protein-coupled P2Y family. For P2X family, seven subtypes have been reported, and a member of this family forms a homo-trimeric structure or a hetero-trimeric structure together with another member of this subtype and functions as a non-specific cation channel (Non-Patent Document 6).
ATP is known to cause pain, and studies with P2X3 knockout and knockdown methodologies have shown that P2X3 receptor mediates transmission of chronic pain. P2X3 receptors are expressed in a specific manner on peripheral sensory nerve to form a homo-complex or hetero-complex with P2X2 (P2X2/3) (Non-Patent Document 1).
Later, the compound A-317491 was reported as a specific antagonist to P2X3 and P2X2/3 receptors. A-317491 is tri-substituted-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]benzamide derivative represented by the formula:
(Patent Document 1). It was reported to exhibit an antagonist activity to P2X3 and P2X2/3 receptors and analgesic action in neuropathic pain model and inflammatory pain model in rats (Non-Patent Document 7). This indicates that pain sensation is transmitted via P2X3 or P2X2/3 receptor and that a compound having a P2X3 or P2X2/3 receptor antagonistic activity is useful as an analgesic. Also, compounds that exhibit P2X3 or P2X2/3 receptor antagonistic activity are described in Patent Documents 2-7.
Additionally, it was recently reported that vesical reflex was strongly reduced in P2X3 knockout mouse (Non-Patent Document 2), suggesting that a compound having P2X3 antagonistic activity is useful in the treatment of diseases caused by overactive bladder. Also, compounds that exhibit P2X3 or P2X2/3 receptor antagonistic activity are described in Patent Documents 2-7.
In addition, P2X3 receptor is expressed in neuroepithelial bodies (NEB) of the lung (Non-Patent Document 9), ATP induces cough (Non-Patent Document 10), and the like, therefore it ie suggested that P2X3 receptor participates in signal transduction in the respiratory system (Non-Patent Document 11). These reports suggest the possibility that compounds that exhibit P2X3 receptor antagonistic activity are useful in the treatment of respiratory diseases.
Later, the compound A-317491 known as a specific antagonist to P2X3 and P2X2/3 receptors was reported inhibiting an activity of afferent vagal A fiber in pulmonary diseases (Patent Document 16). Additionally, biphenyl and phenyl-pyridine derivatives were reported as a specific antagonist to P2X3 and P2X2/3 receptors, and it is suggested that the biphenyl and phenyl-pyridine derivatives exhibit improving effect on respiratory diseases in asthma and lung model (Patent Document 17). Also, compounds that exhibit P2X3 or P2X2/3 receptor antagonistic activity are described in Patent Documents 2-7.
Patent Documents 8, 9, 10, 11, and 15 and Non-Patent Document 14 disclose compounds having similar structure to the compounds of the present invention but they do not disclose analgesic effect and P2X3 or P2X2/3 receptor antagonistic activity. Non-Patent Document 8 discloses compounds having similar structure to the compounds of the present invention and having analgesic effect, but it does not discloses P2X3 nor P2X2/3 receptor antagonistic activity. Patent Document 12 and Non-Patent Documents 12 and 13 disclose compounds having P2X3 receptor antagonistic activity but the structures are different with those of the compounds of the present invention. Patent Documents 13, 14, and 18 disclose compounds having P2X3 or P2X2/3 receptor antagonistic activity with a triazine structure.